Science News, April 29, 2006 by Ben Harder

Just Warming Up

Continued from Friday’s article.

In addition to scoring direct hits against cancer, HIFU may provide assists when used in combination with established drugs. Researchers at the National Institutes of Health’s Clinical Center in Bethesda, Md., showed at last year’s radiology meeting that HIFU can boost the amount of a chemotherapy drug that reaches a tumor. Sergio Dromi and his colleagues injected skin tumor-carrying mice with microscopic envelopes of fat, called liposomes, that contained the anticancer drug doxorubicin. Liposomes carry drugs and other substances into cells.

In some mice, the researchers then used a HIFU machine to deliver intermittent pulses of ultrasound energy to each tumor, elevating its temperature to 42°C and breaking down the liposomes. Examination of the tumors revealed that three times as much doxorubicin reached the target in the HIFU-treated mice as in the other mice.

Other researchers are pursuing HIFU as a method for cauterizing hemorrhaging internal wounds (SN: 1/6/01, p. 12) and breaking up blood clots and kidney stones (SN: 11/26/05, p. 346).

Suarez, the urologist who treated Reinwald in Santiago, anticipates that HIFU may treat pancreatic and kidney cancer, fix heart arrhythmias, and even improve liposuction.

Use of HIFU for cancer could dramatically reduce health care costs, argues Suarez. It requires little or no hospitalization and less recovery time than alternative treatments do. Because HIFU is associated with a low rate of permanent complications, it also decreases the cost of treating those side effects.

“I’m treating about 20 patients a month [with HIFU],” Suarez says. “We are concentrating on prostate cancer fight now. There’s a sense of urgency–it is the most common cancer in men.”

Science News, April 29, 2006 by Ben Harder

Sounding Out Malignancies

Continued from Wednesday’s article.

Unlike fibroids, malignant tumors need to be rooted out entirely if they’re to be beaten. In surgery, doctors remove a specific amount of surrounding healthy tissue to avoid leaving behind any cancer cells. Similarly, in HIFU, doctors may need to kill a veneer of healthy tissue around each tumor, concluded Moshe Papa and Douglas Zippel of Sheba Medical Center in Tel Hashomer, Israel, in the January 2005 Breast Cancer.

Aim and Fire — Inserted into the rectum, an ultrasound device images the prostate (top) and then focuses tumor-killing waves at points inside the gland (bottom).

Those researchers used HIFU to treat 10 women who had breast cancer and were planning to have partial mastectomies. After the procedure, the investigators removed a portion of each treated breast to see whether HIFU had eliminated the tumors. Two volunteers showed no sign of remaining cancer, but eight patients retained at least some cancerous cells at the tumor site. Feng Wu and his colleagues in Chongqing, China, have taken a more aggressive approach. Between 1998 and 2001, they administered HIFU–in combination with either surgery or chemotherapy–to 45 women with breast cancer. They intentionally destroyed a 1.5-to-2-centimeter-thick layer of normal tissue around each tumor.

Five years later, 89 percent of the women had had no recurrence of disease, Wu reported last December at the Radiological Society of North America meeting in Chicago. Wu holds stock in the company that makes the device that his team tested. The study didn’t include a comparison group of similar patients receiving a conventional treatment.

In other studies, it’s not uncommon to find that after surgery and radiation therapy, more than 90 percent of volunteers who have breast cancer go at least 5 years without recurrence.

InSightec-sponsored researchers have begun a trial of HIFU in treating breast tumors and surrounding breast tissue in 200 women in Germany and Japan.

The cosmetic side effects of HIFU are minimal. Since HIFU doesn’t break the skin, it rarely disfigures the breast, Wu says. David Gianfelice of Toronto General Hospital, one of the first North American researchers to use HIFU in breast cancer treatment, notes that third-degree skin burns have resulted in some cases. But recent refinements to the InSightec hardware have minimized that problem, he says.

By delivering “a nice, tight package of heat” to the tumor, MR-guided HIFU might eventually supplant surgery as the treatment in some cases of breast cancer, Gianfeliee says. That same goal applies in prostate cancer, which researchers abroad have been treating with HIFU since the mid-1990s. For example, more than 400 men with early-to-mid-stage prostate cancer have received HIFU as an initial therapy using the device manufactured by EDAP of Vaulx-en-Velin, France.

Andreas Blana and his colleagues at the University of Regensburg in Germany reported results from 146 of these patients, who were tracked for an average of nearly 2 years. Blana’s team reported in the Febmary 2004 Urology that 87 percent of the patients remained free of their cancer. In studies of traditional prostate cancer therapies, up to 95 percent of men with earlystage cancer remain caneerfree at least 5 years after treatment.

At Hachioji Hospital in Tokyo, Toyoaki Uchida and his colleagues have treated more than 200 men since 1999. Overall, 81 percent of the men remained free of disease 1 year after the procedure, and 77 percent had no disease after 5 years, Uchida reported at a meeting of the International Society for Therapeutic Ultrasound in Boston last October.

But more evidence is needed to prove that HIFU rids men of cancer as effectively as established therapies do, says urologist Peter Scardino of Memorial Sloan-Kettering Cancer Center in New York City. Other researchers are now testing HIFU in patients with terminal liver or brain cancer or patients in whom tumors from other organs have spread to bone. These trials are intended to relieve pain.

Please come back on Sunday for the conclusion of the article.

Science News, April 29, 2006 by Ben Harder

Fixing Fibroids

Continued from Monday’s article.

Uterine fibroids are nonmalignant tumors that can impair fertility and sometimes cause pain, heavy menstrual bleeding, and urinary frequency. The condition has traditionally been treated by surgical removal of the uterus, or hysterectomy. This approach definitively rids a woman of fibroids and relieves the pressure that the fibroids had placed on nearby tissues.

In contrast, HIFU “does not totally get rid of the fibroids,” says radiologist Fiona Fennessy of Brigham and Women’s Hospital in Boston. “This isn’t a malignant tumor. All we’re trying to do is improve symptoms”

To minimize risks such as skin burns and damage to healthy internal tissues, radiologists destroy only the center of the fibroid and don’t attempt to heat the surrounding area, called the margin, Fennessy says.

However, because the blood vessels that support a fibroid are concentrated near its core, destroying the center usually eliminates part of the margin, says gynecologist Phyllis Gee, director of the North Texas Uterine Fibroid Institute in Plano.

To evaluate HIFU‘s success, Brigham and Women’s researchers led by gynecologist Elizabeth A. Stewart treated more than 100 women who had fibroids. The team used a machine made by InSightec Ltd. of Haifa, Israel, that incorporates an ultrasound transducer into a magnetic-resonance (MR) scanner.

During treatment, a sedated woman lies facedown on the bed of the scanner. Beneath her abdomen, the ultrasound transducer aims and fires away for up to 3 hours while the MR scanner lets doctors monitor tissue temperature and fibroid position.

Most patients experience a “mild level of pain” during and immediately after procedure, Stewart says.

Stewart’s team reported in the January Fertility and Sterility that 71 percent of the patients treated have a significant reduction in fibroid symptoms for at least 6 months, and 51 percent experience that improvement for at least a year. HIFU doesn’t produce sufficient relief for all women, however. Seventeen percent of the volunteers sought another treatment, such as hysterectomy, within a year, Stewart says.

Women treated with HIFU missed an average of 1.4 days of work after the operation, Stewart says. That compares with 18.9 missed days among women treated by hysterectomy for similar fibroids, Stewart reported in Jerusalem last June to the Israel Society of Obstetrics and Gynecology.

To measure the benefit 3 years after treatment, Gee is leading a new study that will track 70 women with fibroids who received HIFU. InSightec funded both studies.

After reviewing preliminary clinical data, the U.S. Food and Drug Administration in late 2004 approved the InSightec equipment for clinical use in treating fibroids.

Please come back on Friday to continue the article.

Science News, April 29, 2006 by Ben Harder

The Dominican Republic is known among tourists for its white sands, magnificent waterfalls, and unusual wildlife. But none of those was the attraction that drew Charles A. Reinwald. He came for a rendezvous with an ultrasound device. Reinwald had aggressive prostate cancer, and he didn’t care for the treatment options available in the United States. So, one day in late June 2004, Reinwald traveled from his home in Tequesta, Fla., to a hospital in the Dominican city of Santiago. There, a Miami-based urologist directed ultrasonic waves at the patient’s cancerous prostate gland.

The Dominican Republic and various other countries, including Canada, England, and Mexico, permit doctors to treat prostate cancer with a technique called high-intensity focused ultrasound, or HIFU. It often avoids the irreversible side effects, including impotence, that can arise during surgery, radiation, and the other treatments available in the United States.

In the Santiago hospital, urologist George Suarez and his assistants inserted a transducer emitting ultrasonic waves into Reinwald’s rectum. The curved transducer put the waves on converging paths in the same way that a magnifying glass focuses sunlight. Where the streams of energy intersected at the prostate, the temperature soared to more than 80°C, cooking small batches of tumor cells in seconds.

For about 2 hours, the transducer steadily shifted its aim across rows of space. Its progress resembled that of a dot matrix printer applying ink to paper. Tissue just millimeters away from the HIFU target zone remained unharmed.

Reinwald’s cancer isn’t cured, but he hasn’t required medical intervention since the operation. At age 80, he works full-time as president of the Cancer Cure Coalition, a nonprofit organization that he founded in 2000 after his wife’s diagnosis of cancer.

He expresses no regrets about his HIFU treatment. “Why do [surgery] when I have available to me a less toxic treatment?” he asks.

HIFU, however, is not generally available in the United States. It has been approved for only one use: treating uterine fibroids. Suarez and other urologists who treat U.S. men who have prostate cancer do so abroad and charge about $20,000 per case. Patients also need to pay their own way to Santiago, Toronto, or another foreign city, to undergo the procedure.

A handful of companies market HIFU devices. Although they vary in design and therapeutic purpose, all the machines rely on the same underlying principle. They focus ultrasound energy at a point several centimeters away from the transducer and destroy tissue there.

The companies, including US HIFU of Charlotte, N.C., which Suarez partially owns, have funded research to test whether the new approach is safer and more effective for a variety of cancers than standard therapies are. Breast, bone, brain, and liver tumors are among those cancers being treated experimentally with HIFU. Investigators also continue to study the efficacy of the technique in women with fibroids. In each case, physicians must place the transducer within a few centimeters of the target.

While HIFU appears to sidestep some typical side effects of surgery and radiation, it’s not yet clear whether the novel approach is as successful at curing cancers as those standard treatments are. So far, no study has directly compared the ultrasound procedure to an established cancer treatment.

A British government body, the National Institute for Clinical Excellence, maintains that the evidence “appears adequate to support the use of this procedure for prostate cancer.” But it also states in a document that offers guidance to the National Health Service, “The effects of HIFU for prostate cancer on quality of life and long-term survival remain uncertain.”

Please come back on Wednesday to continue the article.

We report cancer related outcomes and treatment related toxicities following HIFU therapy for men with localized prostate cancer.

Materials and Methods

This series comprises 340 patients who were treated with Sonablate® HIFU devices (Focus Surgery, IN, USA) patients with a minimum follow-up of one year. During follow-up, prostatic biopsies and PSA level measurements were performed to determine the failure as 3 consecutive rises in the PSA according to the ASTRO definition. None of the patients received androgen deprivation prior to documenting biochemical failure. Kaplan-Meier curves and log-rank test were used for analysis.

Results

The median age and PSA level were 68 years (range 45-88) and 9.5 ng/ml (range 3.1 to 154), respectively. Stage was attributed as follows: T1c in 173, T2a in 106, T2b in 47 and T3 in 14 patients. The median follow-up period for all patients was 23.2 months (range 3 to 86). The biochemical disease-free survival (bDFS) at 5 years in all patients was 70%. The bDFS at 5 years for patients with low, intermediate and high risk groups were 90%, 65% and 57%, respectively (p<0.0001). The bDFS at 5 years for patients with PSA less than 10 ng/ml, 10-20 ng/ml and more than 30 ng/ml were 88%, 68% and 17%, respectively (p<0.0001). 78% had negative biopsies from a mean of 6 cores 6 months after HIFU.

Conclusions

HIFU appears to be both an effective and well tolerated procedure for men with localized prostate cancer.

Karen Garloch

A Charlotte company that shares ownership of a device used to treat prostate cancer in other countries has received approval to expand testing of the treatment in the United States.

The device, called Sonablate 500, uses high-intensity focused ultrasound (HIFU) as an alternative to surgery.

The treatment is approved in Japan, China and other countries, including most of Europe. But it is still considered experimental for prostate cancer in the United States and can be used here only as part of a clinical trial.

This month, the U.S. Food and Drug Administration approved the Charlotte company’s device for use in a Phase III study to determine effectiveness. The study will involve 466 patients at 24 sites, possibly one in Charlotte.

To qualify, patients must be newly diagnosed with early-stage prostate cancer that has not spread from the walnut-sized gland. Half the patients will receive HIFU, and half will receive cryosurgery, which destroys tissue by freezing it.

Patients will be followed for two years, and results could be available in three years, after which FDA approval will be sought.

“This is the last hurdle toward our goal of bringing HIFU to the United States,” said Steve Puckett Jr., chief executive of Charlotte-based U.S. HIFU. Puckett, 25, is a recent graduate of Vanderbilt University with a bachelor’s degree in history. He has the backing of his father and company founder, Steve Puckett, who also founded two hospital chains, MedCath Corp. and Hospital Partners of America, after working at Carolinas Medical Center in the 1980s.

The younger Puckett became interested in HIFU after meeting Dr. George Suarez, a Miami urologist who had investigated alternative treatments that would be less likely to cause impotence and incontinence.

HIFU delivers focused ultrasound waves to the prostate through a probe inserted into the rectum. A physician at a computer monitor controls the probe, which sends ultrasound waves through the rectal wall to produce intense heat that destroys the targeted cancerous tissue.

Puckett Jr. said HIFU patients recover more quickly than surgical patients, who remain in the hospital for two or three days and take six to eight weeks to recover. “These guys are off the table and two hours later, they’re walking around,” he said.

Suarez, who helped start U.S. HIFU, is medical director of the company and performs the treatment in other countries.

Several Charlotte-area patients have traveled to Mexico and the Dominican Republic for the treatment, and several local doctors have gone there to learn the technique.

Darrell Bunch, 50, of Fort Mill, S.C., said he chose HIFU even though his urologist recommended radical prostatectomy because he wanted to reduce the risk of becoming incontinent. “I was only 48,” Bunch said. “It was a quality-of-life issue.”

Since the treatment, his level of PSA (prostate-specific antigen) has dropped from 10 to 0.01. “You can’t get any lower than that,” he said.

“Considering what my options were, I really think I chose the best,” Bunch said. “It’s a shame that I had to go outside the country. They’ve been doing this in Europe, Germany and Japan for a long time.”

Dr. Chris Teigland, a urologist and researcher at Carolinas Medical Center, spent a weekend in Mexico this spring learning the technique and is negotiating with U.S. HIFU to be part of the Phase III study.

The treatment is “easy on the patients,” Teigland said. “One thing that’s remarkable is how quickly they bounce back.”

Teigland predicted HIFU will be approved for prostate cancer, but whether it becomes the preferred treatment for all patients remains to be seen. “I think it will be a part of the future of treatment choices for patients with prostate cancer… We need data to show us how effective it is.”

A second clinical trial of HIFU for early-stage prostate cancer is being conducted at Duke University using a second device called Ablatherm HIFU.

HIFU is also approved outside the United States for treating pancreatic, breast, liver and kidney cancer. Charlotte Realtor Barbara Tate died in July while in China, where she had traveled to receive the treatment for pancreatic cancer.

HIFU relies on the physical properties of ultrasound energy. For therapeutic purposes it is focused by either an acoustic lens, bowl- shaped transducer or electronic phased array.

As ultrasound propagates through tissue, zones of high and low pressure are created. When the energy density (also known as focal intensity, measured in W/cm2) at the focus is sufficiently high (during the high-pressure phase), tissue damage can occur as a result of thermal coagulation necrosis and/or acoustic cavitation. The volume of a HIFU-generated lesion at the focal point is small (typically 10 mm long by 1–2 mm wide, in a cigar shape orientated along the long axis of the beam). If the intention is to ablate a given volume of tissue, individual lesions are placed next to each other to provide a continuous zone of necrosis.

It was shown experimentally that when mammalian tissue at the focus of a HIFU beam is raised to >60 °C for 3 s, all of the cells in that volume are rendered nonviable⁴. Thethreshold for achieving this is thought to be relatively constant among subjects⁵. Accordingly, algorithms were developed assuming certain tissue-related properties, tissue homogeneity and fixed ultrasound absorption coefficients that aim to produce thermal ablation using predefined power/time combinations at given tissue depths. In reality, the HIFU beam propagates through tissue and tissue interfaces that are characterized by natural variability, e.g. prostates vary among persons in size and in the ratio of stroma to epithelium. This will effect absorption coefficients and attenuation. Moreover, the presence of disease (cancer or no cancer) and the androgenic status of a patient are likely to add to this variability. These facts make it unlikely that an algorithm-based method of treatment will be the most likely to achieve the desired effects in most patients.

It follows therefore that some method is required for adjusting the energy to suit the unique characteristics of the prostate being treated. It is generally accepted that real-time imaging is a desirable attribute for any new minimally invasive therapy⁶, but there is debate about the best method to use. B-mode ultrasonography (US) is the only method in clinical use for monitoring HIFU therapy of the prostate, and this relies on detecting hyperechoic grey-scale changes within the treatment field. These changes are the result of both acoustic cavitation and tissue water vaporization, the latter occurring at boiling point. Grey-scale changes seen on B-mode US were correlated with histological changes within treated tissue during extracorporeal⁷ and transrectal therapy⁸, and their formation postulated for use in the control of prostate ablation⁹, but they have not been formally categorized to aid the clinician in conducting the therapy.

We describe our early experience of HIFU therapy using two distinct approaches to treatment. The first regimen was based on an estimated energy exposure, the algorithm- based approach; the second actively sought to generate grey-scale changes and to use these to guide energy exposure to the prostate. We described this type of treatment as ‘visually directed’. In addition to describing the outcomes of care associated with these two approaches, we propose a standardized nomenclature for the changes seen on B- mode US imaging during HIFU therapy for prostate cancer.

Patients and Methods

Between November 2004 and October 2005, 61 men were treated using the Sonablate500® (Focus Surgery, IN, USA) which consists of a power generator, water-cooling system (the ‘Sonachill®’), a treatment probe and a probe-positioning system (Fig. 1). The probe has two curved rectangular piezoceramic transducers with a driving frequency of 4 MHz and focal lengths of 30 and 40 mm, respectively. During treatment, these can be driven at low energy to provide real-time diagnostic US imaging or at high energy for therapeutic ablation (in situ intensity 1300–2200 W/cm2). The probe is covered by a condom through which cold (17–18 °C) degassed water circulates pumped by the Sonachill.

Thirty-four of the 61 men treated were included in this report (Fig. 2). All had prostate cancer stage =T2 (N0,M0), a PSA level of <15 ng/mL and prostate gland volumes of 1 cm diameter, as visualized by a previous TRUS. Written informed consent was obtained before treatment in all cases, and all men were followed-up for =3 months. It was necessary to exclude from the analysis men who had previously had hormone therapy, as this would confound the PSA nadir recorded after therapy.

Men were prepared before the procedure with two phosphate enemas to empty the rectum; an oral bowel preparation was used in some cases. Treatment was under general anaesthesia in all cases to reduce patient movement and discomfort. Men were placed in the lithotomy position, and the anal sphincter gently dilated. The treatment probe was introduced with a covering of ultrasound gel to couple it to the rectal mucosa, and then held in position by an articulated arm attached to the theatre table. A 16 F Foley urethral catheter was inserted under sterile technique, and a 10 mL balloon inflated to allow accurate visualization of the bladder neck and median sagittal plane.

Axial and sagittal US images were taken through the prostate using the transducer in the diagnostic mode. Treatment planning used proprietary software, which allows the prostate to be divided into ‘blocks’: anterior, middle and posterior, on both right and left sides. The software directs the transducer to move automatically so that the acoustic focus is moved sequentially through each point in the block. Each acoustic pulse ablates a volume of 3 × 3 × 10 mm, by heating the tissue to 80–98 °C almost instantaneously¹⁰, and individual lesions overlap slightly to ‘paint out’ the entire volume, using a combination of 3-s exposures (‘on’) time and 6-s pauses (‘off’) time, during which the gland was visualized with real-time US. The 4-cm focal length probe was used to treat anterior and middle blocks, and the 3-cm probe used to treat the posterior block.

The software is semi-automated, with the amount of energy applied to the prostate remaining under the control of the user. As a result, it is possible to treat the prostate in several ways. For instance, one approach uses pre-set energy exposure levels, the intensity of which depends on the part of the prostate that was being treated, and whether the treatment is a primary or salvage (after radiation) case. To a large extent, these energy exposure levels are derived from animal experiments¹¹ or as a result of outcome monitoring in case series¹². This might be termed an algorithm-based approach. Clinical series using this technique showed that the mean PSA nadirs achievable after treatment were ˜1.4 ng/mL¹³. These results are similar to those achieved by other transrectal HIFU devices that rely on the upper power limit being set without user control¹⁴.

An alternative method of managing energy exposure might involve abandoning any preset criteria to permit the maximum energy exposure deemed to be both effective and safe. This would only be possible if both therapeutic objectives of effectiveness and safety were under the control of the operator, but to a large extent they are. The site intensity at the focal point (the target zone) can be monitored using visual feedback, as evidenced by hyperechoic changes on B- mode US. It is possible to increase energy exposure to obtain these visual changes and to decrease the exposure if the changes become uncontrolled. Our hypothesis is that obtaining visual changes at the focal point can serve as a real-time feed-back to the operator that cytocidal levels of energy are being delivered to the part of the prostate being treated. Implicit in this approach are strong, and we think robust, safety considerations. By controlling the visual change at the threshold level at the focal point, the operator is as certain as possible that the energy is being deposited in the intended area. Moreover, other in-built safety features, such as the reflectivity index in the near field, place an upper boundary on energy absorption in the area abutting rectal mucosa. We termed this approach ‘visually directed’. Using this, the grey-scale changes seen on diagnostic US are actively monitored, and the power adjusted accordingly. For consensus on the types of changes seen, a semiquantitative method of analysis was developed (Appendix), which allows comparison within and between treatments. These ‘Uchida’ changes were named after Toyoaki Uchida (Professor of Urology in Tokai University Hachioji Hospital, Tokyo, Japan) who performed the preliminary clinical work on the Sonablate device.

Using visually directed treatment, the operator aims to generate grey-scale changes throughout the target tissue. During treatment, the power level (energy exposure) is constantly adjusted to achieve Uchida Grade I or II changes (Fig. 3). By obtaining these changes, the operator can control the energy in the target zone that is either on or just below the cavitation threshold. This grey- scale US feedback is also used to provide a ceiling threshold. Grade III changes occur when uncontrolled cavitation occurs in the near field; this is corrected by reducing the energy exposure. Visually directed HIFU therefore takes into account both inter- and intraprostatic differences in acoustic and thermal properties, and allows the user to respond in real-time to the therapy.

Nine men were treated using the algorithm- based protocol (group 1) and 25 men using the visually directed protocol (group 2). All patients were discharged on the day of treatment. Demographic details are given in Table 1; all patients were followed up for =3 months. After therapy, patient status and treatment-related complications were assessed at fixed intervals by visits to the clinic and by telephone consultations with a specialist nurse practitioner. All men were discharged with an indwelling urethral catheter. The PSA level was measured at 3 months after treatment to give a nadir value. Statistical analysis was used to assess the correlation of variables between groups.

Results

Table 1 shows details of the operative variables and results. The difference between the mean PSA nadirs of the groups was significant (P < 0.005). In group 2, 21 of 25 patients achieved PSA nadirs of =0.2 ng/mL at 3 months after treatment; seven patients achieved undetectable PSA values. The mean PSA nadir achieved in group 2 was 0.15 ng/ mL, vs 1.51 ng/mL in group 1.

A trial without catheter was successful at the first attempt in eight of the nine patients in group 1, and 21 of 25 in group 2 (84%). In the 3 months after HIFU, a few patients in each group required flexible cystoscopic investigation. Some also had infective complications, which are listed in Table 1.

Discussion

Visually directed HIFU for organ-confined prostate cancer can produce a low PSA nadir 3 months after the procedure. In the present patients, the mean PSA nadir was significantly lower than that using an algorithm-based protocol for treatment of similar patients, and compares favourably with both brachytherapy and cryotherapy for the treatment of organ-confined prostate cancer^15,16. In the Seattle brachytherapy series¹⁷ 72% of patients with no evidence of disease biochemically achieved PSA nadirs of <0.2 ng/mL, with the mean PSA nadir being 0.25 ng/mL. In the present study we achieved PSA nadirs of =0.2 ng/mL in 84% of patients using the visually directed method, and an undetectable PSA level in just under a third of those treated.

Clinicians familiar with TRUS will acknowledge that the characteristics of prostate glands differ between patients. Even men who have had no previous therapy can have glands of different density and with different patterns of micro- or macro- calcification. Just as the amount of pressure that is required to exert on the scalpel is based upon the real-time characteristics of the tissue it is passing through, so is the amount of energy required to cause ablation within the prostate gland.

We have given the first formal description of grey-scale US changes associated with transrectal HIFU treatment for prostate cancer (Appendix). These ‘Uchida changes’ allow a descriptive analysis of changes seen during therapy and permit a formal system of treatment to be developed, which is consistent between users but flexible according to the gland treated. Grey-scale changes seen on B-mode US have been identified in relation to ablative therapies; these have previously been termed ‘pop-corning’ in relation to HIFU treatment of the prostate, and ‘gas cloud’ formation in relation to radiofrequency ablation in the liver, but have not been quantified for use as a method of real-time feedback.

In the past, cavitation was avoided, as it was assumed to be uncontrollable, and that the risk of cavitation outside the area of interest was too great. Extensive dosimetry studies ^7,18 showed that not only are the grey-scale changes visualized on B-mode US associated with histological ablation, but that single pulses of high-intensity ultrasound can produce well circumscribed, predictable volumes of necrosis. It might be argued that, by producing cavitation, the tissue is being ‘over-treated’; in the absence of other real- time methods of detecting thermal ablation, this remains the best method of treatment monitoring. Tissue elastography¹⁹ and ultrasound thermometry²⁰ are under development but remain experimental; MRI²¹ might accurately detect temperature changes, but MRI devices are costly, do not provide feedback as instantaneously as B- mode US, and have not been used clinically in the setting of transrectal prostate HIFU.

Although presently the diagnostic TRUS uses 7 MHz probes and the 4–6 MHz centre frequency band of the Sonablate-500 is not the standard frequency for diagnostic imaging of the prostate, we have had no difficulty in using it for planning and monitoring treatment. This 4–6 MHz frequency band allows excellent visualization of the prostatic margin and grey-scale changes within the gland. Higher frequency TRUS is used in all patients before treatment, and even with the highest ultrasonic resolution the differentiation between benign and malignant prostate is still inaccurate and therefore unnecessary for the purposes of treatment²².

Despite the few patients in each group, the catheter-free rate appears equivalent between them (>80% at the first attempt) with infective complications in ˜10% of patients. This is consistent with other reports using combined prostatic resection and HIFU²³. After treatment, most patients have short-term irritative voiding symptoms as a result of the sloughing of prostatic tissue via the urethra. In the visually directed group, more patients underwent flexible cystoscopy. In all cases this was done to investigate irritative and obstructive voiding symptoms, with the result that urethral debris was cleared. The threshold for undertaking a flexible cystoscopy is now considerably higher, as most patients are taught intermittent self-catheterization before treatment, which allows the dislodging of prostatic slough with no need for formal intervention.

We assumed a relationship between the PSA nadir at 3 months and treatment outcome. Data assessing this relationship indicate that this is a justifiable association²⁴, but in that study the outcome was likelihood of disease on prostate biopsy at 6 months after treatment. Although it is logical to assume that this affects the long-term outcome, there are no long-term data to verify it at present; certainly the PSA nadir was shown to correlate with longer term outcome in the context of radical surgery and external beam radiotherapy ^25,26.

The present study represents the first reported experience of visually directed HIFU for treating organ-confined prostate cancer. We think that this is the first attempt to standardize the conduct of treatment. Standardization of therapy makes it easier to teach and makes it possible to derive quality standards. Most importantly, standardizing the intervention is the key step in health technology assessment. Once this is done it is possible to start to explore the next phase of investigation, defining the determinants of outcome. This is likely to lead to better case selection and improved conduct of therapy.

Acknowledgements

We are grateful to those at Misonix, Inc. for their ongoing financial support. Rowena Couling (Specialist Nurse Practitioner) for her help with data management and Naren Sanghvi and Focus Surgery for their scientific support.

Conflict of Interest

R. Illing is supported by a grant from Misonix; M. Emberton has acted as a paid consultant to Misonix. Source of funding: Misonix – European distributor of the Sonablate device.

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Correspondence

Rowland O. Illing, The Institute of Urology and Nephrology, University College London, London, UK. e-mail: rowland@doctors.org.uk

Abbreviations

HIFU, high-intensity focused ultrasound; US, ultrasonography.

Appendix

Uchida Changes

We devised a method of assessing grey-scale US changes seen during visually directed therapy to allow quantification and comparison in and between treatments. ‘Uchida changes’ were classified as Grades I, II and III depending on whether hyperechoic regions were identified within individual target treatment zones, became confluent between adjacent HIFU treatment exposures, or were seen migrating outside the target treatment zone, respectively. These were then subclassified into ‘a’, ‘b’ and ‘c’ depending upon whether 50% of the focal region was involved in the changes, respectively (Fig. 3). The aim was to see some form of Uchida change every second or third exposure, to confirm that treatment was taking place on or near the cavitation threshold.

Toyaki Uchida, Sunao Shoji, Yoshihiro Nagata Department of Urology, Tokai University, Hachioji Hospital, 1838 Ishikawa-machi, Hachioji Tokyo 192-0032, Japan

Introduction

HIFU delivers intense ultrasound energy, with consequential heat destruction of tissue at a specific focal distance from the probe without damage to tissue in the path of the ultrasound beam. We evaluated biochemical disease-free survival, predictors of clinical outcome and morbidity in patients with localized prostate cancer treated with HIFU.

Method

A total of 237 consecutive patients underwent HIFU with the use of Sonablate® (Focus Surgery, Indianapolis, USA). The median age and PSA level were 69 years (range 45-88) and 9.50 ng/ml (range 3.39 to 89.60). The TNM stage was T1c in 119 patients, T2a in 84 patients and T2b in 34 patients. The histologic grade was Gleason score 2 to 4 in 25 patients, 5 to 7 in 183 patients and 8 to 10 in 29 patients. Neoadjuvent hormonal therapy was delivered in 134 patients. The median operating time was 128 min (range 55 to 390 min). The median follow up period for all patients was 20.0 months (range 3 to 74). The American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel criteria for biochemical failure, i.e., three consecutive increases in post-treatment PSA after a nadir has been achieved, was used to define biochemical failure. None of the patients received androgen deprivation after HIFU or other anticancer therapy before documentation of a biochemical failure.

Results

The biochemical disease-free rates at 1, 3, and 5 years in all patients were 81%, 77% and 77% respectively. The biochemical disease-free rates at 5 years for patients with pretreatment PSA less than 10 ng/ml, 10.01 to 20.2 ng/ml and more than 20.0 ng/ml were 93%, 75% and 24%, respectively (P<0.0001). The biochemical disease-free rates at 5 years for patients low, intermediate and high risk groups were 97%, 71%, and 64%, respectively (p<0.0001). According to multivariate analyses, preoperative PSA (p<0.0001) was a significant independent predictor of biochemical recurrence. Forty-four (19%) patients developed a urethral stricture, 6 (3%) patients underwent transurethral resection of the prostate for prolonged urinary retention or urethral stricture, 15 (6%) and 2 (0.8%) patients developed epididymitis and a rectourethral fistula. Twenty-four percent (15/462 patients complained of postoperative erectile dysfunction. Retrograde ejaculation was observed in 12% (14/120) of the potent patients. Transient grade I incontinence was observed in one (0.4%) patient.

Conclusions

HIFU therapy appears to be a safe and efficacious minimally invasive therapy for patients with localized prostate cancer, especially those with a pretreatment PSA level than 20 ng/ml.

Departments of Urology, University of Tokai Hachioji Hospital, Hachioji, and *University of Kitasato, Sagamihara, Japan

Introduction

Prostate cancer is the most common malignancy in men and the second leading cause of death from cancer in the USA¹. Radical prostatectomy (RP) has long been regarded as appropriate therapy for patients with organ-confined prostate cancer. Despite excellent 5- and 10-year survival rates after RP, surgery is associated with significant morbidity, e.g. blood loss with transfusion- related complications, erectile dysfunction in 30–70% of men, and stress incontinence in up to 10%^2–5. In addition, surgical intervention is not typically considered for patients whose life-expectancy is<10 years. Recently, several alternative and less invasive treatments have been developed to treat localized prostate cancer. Brachytherapy, cryosurgical ablation of the prostate, three- dimensional conformal radiotherapy, intensity-modulated external beam radiotherapy and laparoscopic RP have been used [6–10]. However, these alternative treatments, except the conformal radiotherapy and intensity-modulated therapy, require at least percutaneous access.

High-intensity focused ultrasound (HIFU) is a noninvasive technique for the thermal ablation of tissue. HIFU can noninvasively induce complete coagulative necrosis of a target tumour, without requiring surgical exposure or insertion of instruments into the lesion. This advantage makes it one of the most attractive potential options for the localized treatment of tumours. Since January 1999, we have been treating localized prostate cancer with transrectal HIFU^{11, 12}; we report the efficacy, safety and predictive preoperative values of HIFU ablation for treating patients with localized prostate cancer.

Patients and Methods

We used the Sonablate™ (Focus Surgery, Inc., Indianapolis, IN, USA) HIFU machine; the treatment module includes the ultrasound power generator, multiple transrectal probes of different focal depth, the probe- positioning system, and a continuous cooling system (Fig. 1). The transrectal HIFU probes use proprietary transducer technology with low-energy ultrasound (4 MHz) for imaging the prostate and to deliver high-energy ablative pulses (site intensity, 1300–2200 W/ cm2). The single piezoelectric crystal alternates between high-energy power for ablative (3 s) and low-energy for ultrasound imaging (6 s).

Before starting the treatment the operator uses longitudinal and transverse ultrasonograms to obtain an image of the prostate and selects the prostate tissue volume to be ablated by a set of cursors on these images. The probe houses a computer- controlled positioning system, which directs each ablative pulse to the targeted region of the prostate. Each discrete HIFU pulse ablates a volume of 3 × 3 × 10 mm of tissue¹³. The total acoustic power is initially set at 24 and 37 W for 3- and 4-cm focal length probes, respectively. The individual focal lesion produces almost instantaneous coagulative necrosis of tissue as the temperature increases to 80–98 °C in the focal zone^{14, 14}. Under computer control, the ultrasound beam is steered mechanically to produce consecutive lesions so that all focal lesions overlap laterally and longitudinally to ensure necrosis of the entire targeted prostate volume (Fig. 2). An automatic cooling device is used during treatment to maintain a constant baseline temperature of<18 °C in the transrectal probe, which helps to prevent thermal injury of the rectal mucosa.

All patients were anaesthetized by epidural or spinal anaesthesia, and placed supine with open legs. A condom was placed over the probe and degassed water was used to inflate the condom, which was covered with ultrasound gel for close coupling of the ultrasound probe to the rectal wall, and the probe was inserted manually into the rectum. The probe was fixed in position by an articulating arm attached to the operating table. After selecting the treatment region of the prostate from the verumontanum to the bladder neck, the treatment was started. Transrectal probes with focal lengths of 3.0 and 4.0 cm were used according to the size of the prostate, as determined by TRUS, with larger glands requiring longer focal lengths. The treatment continued layer by layer (10 mm thick) from the apex to the base (Fig. 2). Usually, three successive target areas (anterior, mid-part and base) were defined to treat the whole prostate. After completing the treatment, a transurethral balloon catheter or percutaneous cystostomy was inserted into the bladder.

The study included patients with stage T1c2bN0M0 localized prostate cancer; those with anal stricture were excluded from the study. None of the patients received adjuvant hormonal and/or chemotherapy. All patients were fully informed of the details of this treatment and provided written consent before HIFU. Beginning in January 1999, 63 patients with clinically localized prostate cancer were treated with HIFU. Evaluations before HIFU included a history, physical examinations, including a DRE, initial PSA level and Gleason score on needle biopsy of the prostate. All patients had a negative radionuclide bone scan and CT of the abdomen and pelvis confirmed that there was no metastatic disease. Tumours were staged using the TNM staging system¹⁵. The characteristics of the 63 patients are listed in Table 1.

Patient status and treatment-related complications were followed using all available means, including periodic patient visits and self-administered questionnaires on urinary continence and erectile function. The serum PSA level was usually assayed every 1–6 months during the follow-up. At 6 months after HIFU a prostate biopsy was taken in all patients. The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition for biochemical failure, i.e. three consecutive increases in PSA level after a nadir, was used to define biochemical failure¹⁶. The time to biochemical failure was defined as midway between the PSA nadir and the first of the three consecutive PSA increases. None of the patients received androgen deprivation after HIFU or other anticancer therapy before documentation of a biochemical failure.

The chi-squared test was used to assess the correlation between variables before and after HIFU. Distributions of biochemical disease- free survival (DFS) times were calculated according to the Kaplan-Meier curves and the log-rank test used to determine the differences between the curves. A multivariate Cox proportional hazards regression model was used to estimate the prognostic relevance of age, clinical stage, Gleason score, volume of the prostate, pretreatment and nadir serum PSA levels on DFS, with P< 0.05 taken to indicate statistical significance.

Results

The prostate was treated in one (50 patients) or two (13) HIFU sessions for a total of 76 procedures in 63 patients (1.2 sessions/ patient). Reasons for repeating the HIFU treatments were: in five patients because we tried different ‘on’ and/or ‘off’ times, e.g. shorter (2 s) and/or longer off (8–12 s) intervals before establishing the standard on (3 s) and off (6 s) interval; in three for residual tumour or PSA increases; two were only treated on the right or left lobe of the prostate; two because they had a large prostate; and one because there was a problem with the HIFU machine. The median (range) operative duration and hospitalization was 149 (55–356) min and 4 (2–20) days, respectively. The gland size decreased from an initial mean volume of 28.6 mL to a final median volume of 14.5 mL (P< 0.001) in a mean of 6.5 (3–23) months. The mean (SD, median) PSA nadir levels were 1.38 (2.55, 0.5) ng/mL.

Of the 63 patients, 47 (75%) were biochemically disease-free during the follow- up; the 3-year biochemical DFS rates for those with a PSA level before HIFU of<10, 10.01–20 and >20 ng/mL was 82%, 62% and 20%, respectively (P< 0.001). The PSA nadir was 4–8 weeks after treatment; the 3-year biochemical DFS rates for patients with a PSA nadir of<0.2 (20 patients), 0.21–1.0 (25) and >1 (18) were 100%, 74% and 21% (log-rank test, P< 0.001), respectively. Risk factors were a PSA level of =10 ng/mL, a Gleason score of =7, and stage T2b disease, with patients at low-risk having none of these factors, at moderate risk having one and at high risk having two or more¹⁷. The 3-year biochemical DFS rates in patients at low, moderate and high risk was 84%, 69% and 51% (P = 0.0295), respectively (Fig. 3). However, there was no statistically significant difference in patients within stage and Gleason score groups.

In the Cox regression analysis, the PSA nadir was a statistically significant variable for prognosis but age, stage, Gleason grading, serum PSA level and prostate volume were not (Table 2). The final follow-up prostate biopsies showed that 55 (87%) of the 63 patients were cancer-free. The main pathological findings of the prostate biopsy at 6 months after HIFU showed a coagulation necrosis and fibrosis.

All patients reported urinary symptoms, e.g. frequency, urgency and difficulty in urination, during the first 2 months after HIFU treatment. The symptoms were transitory and easily managed by medical treatment. Urethral catheters in all patients were removed 1–2 days after HIFU, but were reinserted in those who could not urinate spontaneously, and removal was attempted every 1–2 weeks thereafter. The median (range) urinary catheterization period after HIFU was 14 (0–31) days. Fifteen (24%) patients developed a urethral stricture, two (3%) complained of retrograde ejaculation and two (3%) other patients of epididymitis. One (2%) patient had a TURP for prolonged urinary retention, one (2%) had grade 1 transient incontinence for a month, and one (2%) developed a recto-urethral fistula (Table 3). Eight of the 34 patients who were sexually active complained of erectile dysfunction after HIFU; two of these eight who desired treatment were treated with sildenafil citrate, and recovered.

Discussion

In 1995, Madersbacher et al.¹⁴ reported the effect of HIFU (using the older Sonablate 200 system) in an experimental study of 10 patients with histologically confirmed hypoechoic and palpable localized prostate cancer. In 1996, Gelet et al.^{18, 19} reported a preliminary experience of HIFU using Ablatherm prototype 1.0 (EDAP-Technomed, Lyon, France) for treating localized prostate cancer. They later summarized their clinical outcome, in which there was a complete response in two-thirds of the patients, with no residual cancer and no three consecutive increases in PSA level. More recently, Chaussy and Thuroff²⁰ reported that the combination of TURP immediately before HIFU reduced the treatment-related morbidity, e.g. catheter time, incontinence, urinary infection and the IPPS. In addition, they summarized the clinical outcome using the ASTRO definition, an 84% stability rate in the HIFU group and an 80% rate in the TURP and HIFU group. In 1999, Beerlage et al.²¹ reported results of 143 HIFU treatments using the Ablatherm prototype 1.0 and 1.1 in 111 patients with clinical stage T1–3N0M0 prostate cancer and a PSA level of<25 ng/mL. The first 65 treatments in 49 patients were selective (i.e. a unilateral or bilateral treatment in one or two sessions, depending on the findings from TRUS and biopsies) and the second 78 treatments in 62 patients treated the whole prostate. There was a complete response (defined as a PSA level of<4.0 ng/mL and a negative biopsy) in 60% of the group with the whole prostate treated, and in 25% of the selectively treated patients. In the present study, two patients who were treated selectively in the right lobe of the prostate for adenocarcinoma, identified by a prostate biopsy, showed a gradual increase in PSA level and viable cancer cells in the untreated lobe on prostate biopsy after HIFU. A second HIFU treatment of the whole prostate maintained the PSA at a low level, with a negative biopsy. Recently, many methods of imaging have been analysed for detecting prostate cancer, including TRUS, CT, endorectal coil MRI and multiple biopsies of the prostate under TRUS guidance. However, prostate cancer is a multifocal disease and it is not yet possible to determine the sites of serum PSA level; d, risk group; and e, PSA nadir level. microscopic foci of cancer cells by imaging analysis alone. Therefore, the whole prostate must be treated, as corroborated by the results of the present study and others.

When summarising the present clinical outcome by the ASTRO definition, 75% of the patients were biochemically disease-free. Particularly those patients whose PSA level P = 0.144 before HIFU was<10 ng/mL and with a PSA nadir of<0.2 ng/mL had an 82% and 100% biochemical DFS rate at 3 years after HIFU treatment. In addition, the PSA nadir (P< 0.001) was a significant independent predictor of time to biochemical recurrence in the multivariate analysis.

HIFU treatment with the Sonablate machine is limited to a prostate size of 50 mL with the present device, even when using a longer focal-length probe. It is necessary to develop a longer focal-length probe for treating prostates of >50 mL. Neoadjuvant androgen-deprivation therapy may be useful in larger prostates to reduce the volume of the prostate before HIFU.

After HIFU there were urethral strictures at or near the verumontanum in the prostatic urethra in a quarter of the present patients, treated by internal urethrotomy and/or periodic dilatation with metal sounds. Using TURP after HIFU treatment may be useful to prevent urethral stricture or urinary retention^{22, 23}. A recto-urethral fistula occurred in one patient after the second HIFU treatment. More precise HIFU power control during repeat treatment is needed. A continuous cooling device was applied to keep the rectal mucosa at<18 °C during the procedure, and there was no recto-urethral fistula in any of the patients after using the automatic cooling system.

Generally, the radicality of prostate cancer and preservation of sexual function are always controversial because erectile dysfunction after treatment depends on preserving the neurovascular bundles that are sometimes invaded by the tumour. In the present study, 25% of the patients had erectile dysfunction after HIFU therapy; interestingly, two of the eight affected and who desired treatment recovered with sildenafil citrate. We consider that this rate is lower than after RP^2–5; obviously, further experience is required to confirm this important consideration.

The median hospital stay in the present series was 4 days; this was related to local socioeconomic conditions rather then clinical or technical factors. There is a significant difference in the national insurance systems between Japan and other countries. Usually, 20–30 days of hospitalization is recommended after RP in Japan. However, recent HIFU treatments at our hospital have involved only an overnight stay.

For many reasons, transrectal HIFU appears to be highly attractive as a minimally invasive treatment for localized prostate cancer. With HIFU treatment there is no incision or puncture, it is bloodless, can be delivered on an outpatient basis and is repeatable. It can also be used on patients with local recurrences who have already been treated with RP, cryoablation of the prostate and radiation therapy. In addition, the option of HIFU may be more attractive to the patient who wants to avoid incontinence and erectile dysfunction afterward, to maintain their quality of life. These features, combined with the optional curative effect, provide an ideal treatment for patients with localized prostate cancer. The few patients and the relatively short follow-up in the present series limit any definitive conclusions. We think that the present data suggest that HIFU has considerable potential as a noninvasive treatment for patients with localized prostate cancer.

Acknowledgements

The authors express their appreciation to Mr Y. Shimazaki, S. Kagosaki, K. Yamashita, K. Takai and N.T. Sanghvi for their technical assistance.

Conflict of Interest

None declared.

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Correspondence

Toyoaki Uchida, Department of Urology, Tokai University Hachioji Hospital, 1838, Ishikawa-machi, Hachioji, Tokyo 192–0032, Japan.

George M Suarez*, Miami, FL; Rafael Estrella, Santiago De los Caballeros, Dominican Republic; Carlos Garcia, Puerto Vallarta, Mexico

Introduction and Objective

Treatment options for localized prostate cancer are varied and challenged by the unpredictable diversity of the biologic behavior of the disease. Accepted treatment often times result in compromising the quality of life style with high rates of impotence and incontinence. High Intensity Focused Ultrasound (HIFU), is a novel, minimally invasive alternative, which provides an acceptable cure rate similar to and in some instances greater than standard therapy.

Methods

87 patients diagnosed with T-1 or T-2 carcinoma of the prostate were treated with HIFU.

Criteria

Gleason score 7 or less, PSA 10 or less, volume less than 40 grams. Patients completed pre and post treatment international index of erectile function (IIEF-5), IPSS and incontinence questionnaires. Post treatment PSA, IIEF-5, IPSS and incontinence questionnaires were at 3, 6, 12 and 18 months. Treatment was preformed as outpatient with epidural anesthesia/IV sedation. Average treatment time 2 hours. Catheter time ranged 14-21 days. Follow-up was 12 and 18 months.

Results

Of 87 patients, 70 maintained a PSA of Nadir, 17 had a post treatment PSA = 1 to 2 and have remained stable with increase from 3 month post treatment PSA. Of 87 patients, 84 reported no change in IIEF-5 nor their IPSS. 3 patients reported erectile dysfunction (ED) responsive to PDE-5 inhibitor (Cialis 20 mg). 2 patients reported a moderate degree of ED prior to HIFU even with PDE-5 inhibitors remained similar ED in the post treatment. There was no incidence of incontinence. Urinary tract infection occurred in 3 patients, urinary retention requiring a catheter was seen in 2 patients. 1 for 5 days after initial removal, 1 for 10 days. Stricture in one patient. No other complications were seen.

Conclusions

Prostate cancer remains a major health issue and the optimal treatment equally as challenging. The impossibility to differentiate biologic aggressive from non-aggressive cancer, groups patients to receive non-discriminating treatment that may be over aggressive. Current treatment may lead to a compromise of quality of life, whereas, patients fell the outcome is worse than the cancer itself.

Our preliminary results indicate HIFU as an effective option in treating cancer, while preserving potency and continence. We recognize long term follow-up is vital to appropriately evaluate this technology. The promising outcome of our data and the results of the international literature on HIFU for prostate cancer merit these results be communicated in the urologic community.